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Altamura, S.* ; Müdder, K.* ; Schlotterer, A.* ; Fleming, T. ; Poschet, G.* ; Qiu, R.* ; Hammes, H.P.* ; Nawroth, P.P. ; Muckenthaler, M.U.*

Iron aggravates hepatic insulin resistance in the absence of inflammation in a novel db/db mouse model with iron overload.

Mol. Metab. 51:101235 (2021)

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OBJECTIVE: The molecular pathogenesis of late complications associated with type 2 diabetes mellitus (T2DM) is not yet fully understood. While high glucose levels indicated by increased HbA1c only poorly explain disease progression and late complications, a pro-inflammatory status, oxidative stress and reactive metabolites generated by metabolic processes were postulated to be involved. Individuals with metabolic syndrome (MetS) frequently progress to T2DM, whereby 70% of T2DM patients show non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, and insulin resistance (IR). Epidemiological studies have shown that T2DM and steatosis are associated with alterations in iron metabolism and hepatic iron accumulation. Excess free iron triggers oxidative stress and a switch towards a macrophage pro-inflammatory status. However, so far it remains unclear if hepatic iron accumulation plays a causative role in the generation of IR and T2DM or whether it is merely a manifestation of altered hepatic metabolism. To address this open question, we have generated and characterized a mouse model of T2DM with IR, steatosis and iron overload. METHODS: Lepr^db/db mice hallmarked by T2DM, IR and steatosis were crossed with Fpn^wt/C326S mice with systemic iron overload to generate Lepr^db/db/Fpn^wt/C326S mice. The resulting progeny was characterized for major diabetic and iron-related parameters. RESULTS: We show that features associated with T2DM in Lepr^db/db mice, such as obesity, steatosis or insulin resistance reduce the degree of tissue iron overload in Fpn^wt/C326S mice, suggesting an 'iron resistance' phenotype. By contrast, we observe increased serum iron levels that strongly exceed those in the iron-overloaded Fpn^wt/C326S mice. Increased hepatic iron levels induce oxidative stress and lipid peroxidation and aggravate insulin resistance, as indicated by diminished IRS1 phosphorylation and AKT activation. Additionally, in the liver we observe gene response patterns indicative of de novo lipogenesis and increased gluconeogenesis as well as elevated free glucose levels. Finally, we show that iron overload in Lepr^db/db/Fpn^wt/C326S mice enhances microvascular complications observed in retinopathy, suggesting that iron accumulation can enhance diabetic late complications associated with the liver and the eye. CONCLUSION: Taken together, our data show that iron causes the worsening of symptoms associated with the metabolic syndrome and T2DM. These findings imply that iron depletion strategies together with anti-diabetic drugs may ameliorate insulin resistance and diabetic late complications.

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